RESEARCH PROJECT 2 SUMMARY JULY 2017-JUNE 2023 Men having sex with men (MSM) and transgender women (TGW) are the most affected populations by HIV, present high prevalence of KSHV and HPV, and two malignant conditions associated to these virus (Kaposi Sarcoma and Anal Squamous Cell Carcinoma, respectively) are also disproportionally affecting these groups. KS continues being the most important AIDS associated cancer in LMICs. On the other hand, ART changed the course of HIV and increased life expectancy, but HPV persistence represents a continued risk factor for anal cancer. The aims of this project are 1) to increase the knowledge about prevalence, incidence, and clearance of KSHV and HR-HPV among high risk individuals (MSM and TG individuals with and without HIV) and factors associated to clinical progression 2) to create a repository of prospective and retrospective samples of KS and ASCC cou- pled to clinical data and 3) to explore in KS and ASCC the molecular portrait and viral factors by Whole-Exome sequencing in parallel with RNA-Seq profiling comparing the mutational and gene expression profiles of samples for identify specific transcriptome. We will accomplish these aims studying two populations: a) a cohort of individuals at high risk of developing KS and ASCC 220 MSM and 110 transgender women, HIV positive and HIV negative) in whom we will assess every 6 months during 4 years the prevalence, incidence, and associated factors for KSHV infection and HPV infection. c) a repository of clinical information and biological samples of individual with KS and ASCC. This registry will involve two components, the prospective component that will collect clinical data and samples from patients in study for KS or ASCC (15-30/year) and a retrospective component aimed to provide limited clinical information and remnants of pathological specimens at 6 sites (400 KS and 200 ASCC). All the material will be available also for Basic and Translational Projects 1 and 2. With these aims our research contributes to several areas defined by NIH as high priority research on HIV/AIDS, including the focus in malignances, basic research on genetic determinants of co-morbidities and research to reduce health disparities in the treatment outcomes of people living with HIV. Further, this research will support research capacity development in a low- and middle-income settings. Accordingly, we aim to address several urgent health questions, which will inform the development of a range of policies and interventions throughout South and North America. The long-term objective of this study is to catalyze international collaboration among US and Argentinean investigators to improve capacity to reduce the cancer burden among HIV individuals.